OVERVIEW
Hypercalcemic nephropathy is a renal tubulointerstitial lesion caused by hypercalcemia (>2.75 mmol/l) and/or hypercalciuria (excess calcium in the urine), which may be severe enough to attending a decrease in glomerular filtration rate. Clinical manifestations are characterized by three major syndromes: renal tubular dysfunction, renal failure (acute or chronic) and urinary stones. Some patients with hypercalcemic nephropathy may have systemic multi-system soft tissue calcification at the same time. Localized calcification caused by the kidney itself, sponge kidney, etc. are not included in this scope.
Etiology
Changes in serum calcium concentration are mainly related to changes in the function of three organs: bone, renal tubules and intestine. In turn, the functions of these organs related to calcium and phosphorus metabolism are regulated by endocrine hormones such as parathyroid hormone, 1.25(OH)2 vitamin D3 and calcitonin. Thus, elevated serum calcium concentrations are often associated with increased calcium release from bone, increased intestinal calcium absorption, or decreased urinary calcium excretion; at the same time, they are associated with excessive concentrations of parathyroid hormone (PTH) or 1.25(OH)2 vitamin D3 in the body. The causes of hypercalcemia can be seen in the table. Hypercalciuria, on the other hand, is associated with decreased renal tubular calcium reabsorption and increased urinary calcium excretion (percentage of calcium excreted in urine).
Causes of hypercalcemia:
1. Excess parathyroid hormone
Primary hyperparathyroidism,Severe secondary hyperparathyroidism (tertiary hyperparathyroidism),Ectopic PTH secretion.
2. Hypervitaminosis D
Vitamin D toxicity (including medical hypervitaminosis D), chronic sarcoidosis, nodular disease, tuberculosis, histoplasmosis, malignant lymphoma.
3. Increased bone resorption
Bone metastasis of malignant tumors, commonly seen in multiple myeloma, breast cancer, prostate cancer, etc.
4. Increased calcium reabsorption in renal tubules.
Familial low urinary calcium hypercalcemia, application of thiazide diuretics.
5. Others
Hyperthyroidism, vitamin A overdose; Addison’s disease, acromegaly, vasoactive intestinal peptide tumors (VIP tumors), lactalkine syndrome, inappropriate application of drugs (aminophylline, estrogens and anti-estrogenic agents, androgens, etc.).
Among the causes of hypercalcemia, hyperparathyroidism is the most common, followed by hypercalcemia due to malignant tumors, as well as hypervitaminosis D and tuberculosis.
Symptoms
In addition to the manifestations of primary disease, hypercalcemic nephropathy is mainly characterized by symptoms of hypercalcemia, renal damage (including renal tubular dysfunction, acute and chronic renal failure, urinary stones, etc.), as well as multi-system soft tissue calcification.
1. Performance of hypercalcemia
Symptoms of hypercalcemia are related to the speed and degree of elevation of blood calcium and the patient’s tolerance of high blood calcium, as well as related to the primary disease. When the blood calcium concentration is 2.75-3.0mmol/L, it is mild hypercalcemia, and most of the patients are asymptomatic or have mild symptoms. Blood calcium 3.0 to 3.5 mmol/L is moderate, and most have clinical symptoms. In the early stage, there are symptoms of polyuria, nocturia, thirst, polydipsia, and even dehydration. When blood calcium exceeds 3.5～4.0mmol/L for severe hypercalcemia, then several systems show obvious clinical symptoms, and even hypercalcemia crisis.
(1) Symptoms of various systems: muscle weakness of the limbs, difficulty in holding objects with both hands, difficulty in walking with the lower limbs; anorexia, nausea, vomiting, constipation, complicated by ulcer disease and gastrointestinal bleeding and perforation; indifference, drowsiness, rigidity, delirium, convulsions, or coma in severe cases, but most of them do not have localized localized symptoms of the nervous system; hypertension, myocardial ischemia, shortening of QT intervals, and disturbances of the cardiac rhythm (premature beats, or even atrial fibrillation, ventricular fibrillation, and etc.), Heart failure.
(2) Hypercalcemia crisis Hypercalcemia crisis occurs when the blood calcium rises sharply to more than 3.7mmol/L (15mg/dl). The patient may have consciousness disorder, coma, intractable hypertension, cardiac rhythm disorder, atrial fibrillation, heart failure, progressive oliguria, acute renal failure, dehydration and electrolyte disorder. If not rescued in time, it can be life-threatening.
2.Renal damage performance
Hypercalcemic nephropathy mainly manifests as renal tubular-interstitial dysfunction, acute and chronic renal failure and urinary stones. Renal tubular-interstitial damage is the main sign of hypercalcemic nephropathy. Persistent hypercalcemia can cause renal histologic changes in a short period of time, mainly involving the ascending branches of the medullary loops, the distal renal tubules and the collecting tubules. Calcium ions are first concentrated and deposited in the renal medulla and enter the epithelial cells of the renal tubules, causing cell degeneration, necrosis, and possible detachment from the basement membrane, leading to occlusion of the renal tubules, and their proximal dilatation. The course of the disease migrates too long, renal tubular atrophy, interstitial fibrosis and other chronic interstitial nephritis and other changes. Eventually involving the glomerulus, glomerulonephritis, fibrosis. Clinically, early polyuria, hypotonic urine, renal glycosuria, amino aciduria, tubular proteinuria, often accompanied by dehydration, hypokalemia, hypomagnesemia. In primary hyperparathyroidism, there is mostly hypophosphatemia, and with vitamin D overdose, blood phosphorus may be elevated. In primary hyperparathyroidism, metabolic hyperchloremic acidosis is often present due to inhibition of renal tubular HCO3- reabsorption by PTH. In other etiologies, metabolic alkalosis is caused by hypercalcemia, which inhibits PTH secretion and increases renal tubular HCO3- reabsorption.
Due to hypercalcemia causing renal vasoconstriction, decreased glomerular filtration rate, tubular blockage caused by renal tubular epithelial cell detachment and crystallization, as well as dehydration and decreased renal blood flow, acute renal failure or chronic renal failure can be caused by acute exacerbation. Prolonged hypercalcemia, renal parenchymal calcium salt deposition, and ultimately bilateral renal atrophy, and lead to chronic renal failure. Urinary calcium increases in hypercalcemia and is easily complicated by stones.
3. Multi-system soft tissue calcification
When serum calcium and phosphorus concentrations increase and their product exceeds 60 to 70 (mg/dl), ectopic calcium salt deposition is likely to occur. Ectopic calcification is more likely to occur in the vascular wall, periarticular joints, myocardium, alveolar wall, gastric wall, renal parenchyma, etc., and corresponding dysfunction occurs.
Examination
1. Blood test
Hypercalcemia, hypophosphatemia, hypokalemia, hyponatremia, hypomagnesemia, hyperchloremia, renal tubular acidosis, increase in BUN and creatinine, decrease in creatinine clearance, and increase in serum alkaline phosphatase and PTH levels can be found.
2. Urinalysis
Proteinuria is mostly mild, dominated by low molecular proteinuria, routine urine examination sometimes see red blood cells, white blood cells, cell tubular pattern, occasionally see calcium tubular pattern. Urinary calcium is increased, higher than 7.5mmol/24h in men, higher than 6.2mmol/24h in women. if hypercalcemia is accompanied by low urinary calcium excretion rate, FEca<1.0%, then the diagnosis of familial hypocalcemic hypercalcemia can be made.
3. Imaging examination
Ultrasound, CT, and MRI imaging examinations can detect primary or secondary hyperparathyroidism and determine the location of the lesion. Renal stones or calcification can also be detected. 99mTc-MIBI (methoxyisobutyl isobaric isotope) isotope scintigraphy can effectively show the location of parathyroid lesions.
Diagnosis
Normal adult serum total calcium reference range is 2.25 to 2.75 mmo1/L. Serum calcium concentration higher than 2.75 mmo1/L is called hypercalcemia. According to the blood calcium level is divided into mild, moderate and severe, mild: blood calcium 2.75～3.Ommo1/L (11～12mg/dl); moderate: blood calcium 3.0～3.5mmol/L (12～14mg/dl); severe: blood calcium>3.5mmo1/L (>14mg/dl, when the blood calcium level ≥3.75mmo1/L (≥15mg/dl) it is called hypercalcemic crisis. However, the reference value is different for different tests, and generally higher than the upper limit of the reference value can be diagnosed as hypercalcemia.
Anyone with unexplained hematuria not accompanied by significant proteinuria should be asked about family history of urinary calculi, and at the same time take a random urine specimen 2 hours after breakfast to measure urinary calcium and creatinine. If the urinary calcium/creatinine is >0.18-0.21, and then the urine is retained for 24 hours, and the urinary calcium is measured to be >0.1 mmol/L, then the diagnosis of hypercalciuria can be made.
In general, if the patient has significant hypercalcemia and presents with symptoms such as polydipsia and polyuria as well as impairment of renal function, the diagnosis is not difficult. However, care should be taken to differentiate it from chronic glomerulonephritis, chronic renal meningitis, hypokalemic nephropathy and uremia.
Treatment
The various triggers of hypercalcemia should be actively controlled, including prevention of excessive sun exposure, restriction of vitamin D and calcium intake, and avoidance of thiazide diuretics (as they increase renal tubular calcium reabsorption).
Prompt removal of the cause is essential treatment. Mild hypercalcemia without symptoms does not require specific treatment, except for proper hydration and restriction of calcium-salt diet.
Those with blood calcium >3mmol/l (12mg/dl), especially when hypercalcemia is critical, need to actively lower calcium treatment to prevent life-threatening conditions and to buy time to create favorable conditions for the treatment of the primary disease. Specific measures are as follows:
1. Volume expansion and diuretic treatment
Firstly, saline should be supplemented to correct dehydration, increase renal blood volume and promote urinary calcium excretion. At the same time and with loop diuretics (such as furosemide), in order to inhibit the medullary loop ascending branch and other parts of water and sodium reabsorption, reduce the cardiac load, and promote urinary calcium excretion.
2. Inhibition of intestinal absorption of calcium salts
Glucocorticoids can inhibit vitamin D activity, inhibit the synthesis of vitamin D by monocytes in granulomas, thus inhibiting intestinal calcium absorption and inhibiting renal tubular reabsorption of calcium salts and increasing urinary calcium excretion. Hydrocortisone, or methylprednisolone can be given as a sedative treatment, usually applied for 3-5 days. Prednisone can also be taken orally for a short period of time, usually 3 to 7 days.
3. Inhibit the absorption of bone calcium
Calcitonin acts on the calcitonin receptor of osteoclasts to inhibit bone resorption by osteoclasts, and at the same time reduces calcium reabsorption in renal tubules and increases urinary calcium excretion. Salmon calcitonin and eel calcitonin are commonly used.
4. Other drugs
Calcium complexing agent EDTA is suitable for fatal heart rhythm disorder.
5. Dialysis
For acute and severe hypercalcemia, such as hypercalcemic crisis, especially blood calcium >4.5mmol/l (18mg/dl), and/or with renal failure. Calcium-free or low-calcium dialysis solution can be used for hemodialysis to achieve rapid reduction of blood calcium.